Overt immune activation is associated with AIDS. Given their proven activity in suppressing immune responses, CD4+CD25+FoxP3+ Treg cells may play an important role in HIV-1 diseases progression; With the CD4 receptor and CCR5/CXCR4 coreceptors, Treg cells are shown to support efficient HIV-1 replication in vitro (or FIV replication in cats in vivo). The goals of the project are to elucidate the molecular mechanisms by which FoxPS differentially modulates T cell activation and HIV gene expression, and to define potential targets/methods for immunotherapeutic intervention. FoxPS determines the development and function of regulatory T cells, which play an important role in. modulating immune responses to pathogens. Our preliminary results show that Treg cells support higher levels of HIV-1 gene expression than CD4+CD25- helper Th cells. Interestingly, FoxPS enhances HIV LTR activity (but inhibits IL2 expression) in human T cells via specific LTR sequences including the NFkB enhancer core. We also show that FoxPS alters the NFAT and NFkB activity to differentially modulate T cell activation and HIV-1 gene expression. A unique NFkB activity is implicated in the FoxPS activity that involves histone acetylation and the Nucleosome Remodeling and histone Deacetylase (NuRD) complex. In addition, FoxPS may interact with linker histones to modulate chromatin structure. I hypothesize that, in order to replicate in FoxP3+CD4+CD25+ Treg cells, HIV-1 has evolved its LTR to be resistant to FoxPS-mediated mechanisms that inhibit IL2 expression in Treg cells. Elucidation of the molecular mechanism of the divergent effect of FoxPS on the highly related IL2 and HIV-1 LTR promoters will help us understand how HIV-1 replicates in Treg cells as well as how FoxPS functions to program Treg cells. First, we will elucidate the mechanisms that mediate HIV LTR enhancement by FoxPS in T cells. We will define the specific sequences in the HIV LTR that respond to FoxPS in Treg cells, and the trans-activating factors that interact with the "FoxPS-response elements". Specific signal transduction pathways and host factors will also be analyzed for their contribution to the enhancement. Second, the epigenetic regulation of the IL2 gene and LTR activity by FoxPS will be investigated. Third, I propose to study FoxPS-mediated chromatin structure alterations in modulating IL2 and HIV gene expression and in Treg lineage determination. The strength of the proposal includes 1) this project addresses one of the most critical questions in HIV-1 immuno-pathogenesis. We will investigate the most fundamental molecular mechanisms of FoxPS in modulating T cell activation and HIV replication in Treg cells. The findings will not only facilitate our understanding of Treg biology, but also shed light on development of novel therapeutics such as immune modulation and vaccines. 2) The proposal is based on our extensive preliminary results, the PI/co-PI's established experience in studying T cell activation, HIV replication and signal transduction, and epigenetic regulation. 3) We will employ or develop a number of novel technologies, reagents and assays for the project. 4) The PI (Su-UNC), co-Pi (Zhang-UNC) and collaborators (Baldwin-UNC and Fu-UCSD) form a team with complementary expertise to address the questions with different perspectives/resources.